p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria

PINK1 and Parkin were first identified as the causal genes responsible for familial forms of early-onset Parkinson's disease (PD), a prevalent neurodegenerative disorder. PINK1 encodes a mitochondrial serine/threonine protein kinase, whereas Parkin encodes an ubiquitin-protein ligase. PINK1 and...

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Bibliographic Details
Published in:Genes to cells : devoted to molecular & cellular mechanisms 2010-08, Vol.15 (8), p.887-900
Main Authors: Okatsu, Kei, Saisho, Keiko, Shimanuki, Midori, Nakada, Kazuto, Shitara, Hiroshi, Sou, Yu-shin, Kimura, Mayumi, Sato, Shigeto, Hattori, Nobutaka, Komatsu, Masaaki, Tanaka, Keiji, Matsuda, Noriyuki
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - deficiency
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Age
aggresomes
Biocatalysis
Cell Nucleus - metabolism
Cells, Cultured
DNA, Mitochondrial - genetics
Embryo fibroblasts
HeLa Cells
Humans
Microtubules
Mitochondria
Mitochondria - metabolism
Molecular modelling
Movement disorders
Mutation
Neurodegenerative diseases
Original
Parkin protein
Parkinson's disease
Protein Folding
Protein kinase
PTEN-induced putative kinase
Sequestosome-1 Protein
Ubiquitin
Ubiquitin - metabolism
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:PINK1 and Parkin were first identified as the causal genes responsible for familial forms of early-onset Parkinson's disease (PD), a prevalent neurodegenerative disorder. PINK1 encodes a mitochondrial serine/threonine protein kinase, whereas Parkin encodes an ubiquitin-protein ligase. PINK1 and Parkin cooperate to maintain mitochondrial integrity; however, the detailed molecular mechanism of how Parkin-catalyzed ubiquitylation results in mitochondrial integrity remains an enigma. In this study, we show that Parkin-catalyzed K63-linked polyubiquitylation of depolarized mitochondria resulted in ubiquitylated mitochondria being transported along microtubules to cluster in the perinuclear region, which was interfered by pathogenic mutations of Parkin. In addition, p62/SQSTM1 (hereafter referred to as p62) was recruited to depolarized mitochondria after Parkin-directed ubiquitylation. Intriguingly, deletion of p62 in mouse embryonic fibroblasts resulted in a gross loss of mitochondrial perinuclear clustering but did not hinder mitochondrial degradation. Thus, p62 is required for ubiquitylation-dependent clustering of damaged mitochondria, which resembles p62-mediated 'aggresome' formation of misfolded/unfolded proteins after ubiquitylation.
ISSN:1356-9597
1365-2443
DOI:10.1111/j.1365-2443.2010.01426.x